As he addressed an audience of virologists from China, Australia, and Singapore at October’s Pandemic Research Alliance Symposium, Wei Zhao introduced an eye-catching idea.
The gene-editing technology Crispr is best known for delivering groundbreaking new therapies for rare diseases, tweaking or knocking out rogue genes in conditions ranging from sickle cell disease to hemophilia. But Zhao and his colleagues at Melbourne’s Peter Doherty Institute for Infection and Immunity have envisioned a new application.
They believe Crispr could be tailored to create a next-generation treatment for influenza, whether that’s the seasonal strains which plague both the northern and southern hemispheres on an annual basis or the worrisome new variants in birds and other wildlife that might trigger the next pandemic.
Crispr can edit the genetic code—the biological instruction book that makes life possible—within the cells of every living being. That means it can take different forms. The best-known version is mediated by the Cas9 enzyme; this can fix errors or mutations within genes by cutting strands of DNA. But virologists like Zhao are more interested in Cas9’s less famous cousin, the Cas13 enzyme, which can do the same to RNA. In human cells, RNA molecules carry instructions from DNA to make proteins, but the genetic code of influenza viruses is composed entirely of RNA strands—a vulnerability that Cas13 can exploit.
“Cas13 can target these RNA viruses and inactivate them,” Zhao explained.
Human cells do not naturally make either Cas9 or Cas13; both of these enzymes are found in the immune systems of bacteria and microscopic organisms called archaea, where Cas13 enables them to disable invading viruses called phages. Zhao and a wider team of scientists are devising an innovative system to confer the same benefits to humans.
Initially pioneered in the lab as a novel Covid antiviral, their idea is to develop a nasal spray or an injection that uses lipid nanoparticles to deliver molecular instructions to flu-infected cells in the respiratory tract. It’s a two-stage process. The first molecule would be an mRNA that instructs the cells to make Cas13, with the second being a so-called guide RNA that directs Cas13 to a specific part of the influenza virus’s RNA code.
“Cas13 then cuts the viral RNA, disrupting the virus’s ability to replicate and effectively stopping the infection at the genetic level,” says Sharon Lewin, an infectious diseases physician at the Peter Doherty Institute who is leading the project.
While the main aim would be to use the technology as a way of curbing short-term infections, Zhao also envisions the spray being used to prevent infections, for example during a particularly virulent flu season. “You’d basically be preparing the cells in your respiratory tract to produce this Cas13, as a first layer of defense,” he says. “It’s like the army—you’d have those soldiers armed and ready to meet their enemy.”
The main attraction of this idea is that Cas13 can be engineered, via the guide RNA, to target so-called conserved regions of influenza’s genetic code. Those are known segments of RNA that are found in virtually all flu strains and are crucial to the virus’s survival. Conventional antivirals such as Tamiflu only target particular strains of flu, which swiftly acquire resistance.
Crispr-Cas13 is one of the leading innovations among so-called pan-fluenza antivirals, but there are others too. Monoclonal antibodies are also designed to target conserved regions of influenza’s genetic code, while other drugs aim to ramp up the production of interferons, the body’s inbuilt alarm system that signals immune cells to attack an invading pathogen.
